Turk J Biochem 2018; aop
Research article
Eren Vurgun*, Osman Evliyaoğlu and Müberra Vardar
Assessment of vitamin D deficiency
level by the physiological response of
parathyroid hormone in Turkish adults
Erişkin Türk toplumundaki D vitamini eksiklik sınır
değerinin paratiroid hormonun fizyolojik yanıtı ile
belirlenmesi
https://doi.org/10.1515/tjb-2017-0265
Received July 10, 2017; accepted December 26, 2017
Abstract
Objective: We aimed to contribute to the literature by
determining deflection point of parathyroid hormone
(PTH) level compared to 25-hydroxy vitamin D3 (25(OH)D3)
level for determining the cut-off value of vitamin D defi-
ciency level in Turkish adults.
Methods: The levels of 25(OH)D3 and intact parathyroid
hormone (iPTH) which were requested simultaneously
in 1 year of 1684 adults were evaluated retrospectively.
25(OH)D3 levels were first classified as 80–50, 50–30, 30–
25, 25–20, 20–15, 15–10, 10–5, 5–0 ng/mL and iPTH levels
among those groups were compared.
Results: First significant difference in iPTH levels was
determined between 25(OH)D3 groups of 80–50 and
50–30 ng/mL (p = 0.007). Second and third significant
differences were determined between 25(OH)D3 groups of
15–10 and 10–5 ng/mL and between 10–5 and 5–0 ng/mL,
respectively (p = 0.006 and p = 0.035, respectively).
There were no differences in iPTH levels among seasons
(p = 0.11).
Conclusion: In the light of these findings; we can state that
iPTH levels are suppressed when 25(OH)D3 over 50 ng/mL,
*Corresponding author: Eren Vurgun, Department of Medical
Biochemistry, Okmeydani Training and Research Hospital,
Sisli, 34384, Istanbul, Turkey, Phone: +905377188596,
Fax: +902122217800, e-mail: eren_vurgun@hotmail.com.
http://orcid.org/0000-0002-2288-1123
Osman Evliyaoğlu and Müberra Vardar: Department of Medical
Biochemistry, Okmeydani Training and Research Hospital,
Istanbul, Turkey, e-mail: oevliya@hotmail.com (O. Evliyaoğlu),
mu-vardar@hotmail.com (M. Vardar)
remains stable when 25(OH)D3 levels in between 50–10
ng/mL and gives the first increase response when 25(OH)
D3 falls below 10 ng/mL. We believe that cut-off value
for vitamin D deficiency in Turkish adults at all seasons
depending on PTH response should be used as 10 ng/mL.
Keywords: Vitamin D; Vitamin D deficiency; Parathyroid
hormone; Seasonal; Calcium.
Özet
Amaç: Paratiroid hormon (PTH) düzeyinin, 25-hidroksi
vitamin D3 (25(OH)D3) düzeyine göre defleksiyon (sapma)
noktasını saptayıp, erişkin Türk toplumundaki D vitamini
eksiklik sınır değerini tespit edip literatüre katkıda bulun-
mayı amaçladık.
Yöntem: Bir yıllık sürede 1684 erişkinin eş zamanlı olarak
istenmiş ve çalışılmış olan 25(OH)D3 ve intakt paratiroid
hormon (iPTH) sonuçları retrospektif olarak değerlendir-
meye alındı. 25(OH)D3 düzeyleri ilk olarak; 80–50, 50–
30, 30–25, 25–20, 20–15, 15–10, 10–5, 5–0 ng/mL olarak
sınıflandırıldı ve bu gruplar arasındaki iPTH düzeyleri
karşılaştırıldı.
Bulgular: iPTH düzeylerindeki ilk anlamlı farklılık, 25(OH)D3
düzeyleri 80–50 ile 50–30 ng/mL grupları arasında tespit
edildi (p = 0.007). İkinci ve üçüncü anlamlı farklılıklar
ise sırasıyla; 25(OH)D3 düzeyleri 15–10 ve 10–5 ng/mL ile
10–5 ve 5–0 ng/mL grupları arasında saptandı (sırasıyla;
p = 0.006 ve p = 0.035). Mevsimlere göre iPTH düzeyleri
arasında anlamlı bir farklılık bulunmadı (p = 0.11).
Sonuç: Bu bulgular ışığında iPTH düzeylerinin; 25(OH)D3
düzeyleri 50 ng/mL’nin üstüne çıktığında baskılandığını,
50–10 ng/mL arasında iken stabil kaldığını, 10 ng/mL’nin
altına indiğinde ise ilk artış yanıtını verdiğini ifade edebili-
riz. PTH yanıtına bağlı olarak, erişkin Türk toplumundaki
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2 Eren Vurgun et al.: Assessment of vitamin D deficiency level by PTH
D vitamini eksiklik sınır değerinin tüm mevsimlerde 10
ng/mL olarak kullanılması gerektiğini düşünmekteyiz.
Anahtar Kelimeler: D vitamini; D vitamini eksikliği; Para-
tiroid hormon; Mevsimsel; Kalsiyum.
Introduction
As the information on the physiological effects of
vitamin D and its roles in other metabolic pathways have
increased, it has become more important to determine and
evaluate vitamin D levels [1]. Vitamin D deficiency and its
effects on human health is still a hot topic which is in the
focus of interest of the entire world [2–4]. However, the
definition of vitamin D deficiency has not been fully dem-
onstrated yet [5]. The most appropriate parameter indicat-
ing the D vitamin status of the individual is accepted as
the 25-hydroxy vitamin D (25(OH)D) [5].
Traditionally, vitamin D deficiency is defined as serum
25(OH)D level <10 ng/mL (<25 nmol/L) because the values
below this level are associated with rickets or osteoma-
lacia [6–8]. World Health Organization (WHO) defined
vitamin D levels below 20 ng/mL (50 nmol/L) as insuffi-
ciency and vitamin D levels below 10 ng/mL (25 nmol/L)
as deficiency [9]. However; Pediatric Endocrine Society,
Endocrine Society and the American Institute of Medicine
organizations have adopted different vitamin D insuffi-
ciency and deficiency values ranging between 10 ng/mL
(25 nmol/L) and 30 ng/mL (75 nmol/L) [10–12].
In studies conducted in adults; these values are
usually based on association of vitamin D levels with frac-
ture risk, intestinal calcium absorption or bone mineral
density [2, 3, 13–16]. In addition to these studies, when
the selected values fall below this levels with their defini-
tions varying in the range of 25(OH)D level 15–30 ng/mL
(37.5–75 nmol/L), it is supported metabolically to observe
increasing serum parathyroid hormone (PTH) levels [14,
16–19].
It is well known that there is an inverse relationship
between 25(OH)D and serum PTH levels [14, 20]. Therefore,
the deflection point of PTH level compared to the 25(OH)D
level will give a good information in terms of sufficiency
and deficiency definitions of vitamin D. Some studies
in which vitamin D deficiency and insufficiency cut-off
values are defined clinically are based on levels maximal
suppression of PTH by 25(OH)D as it is the most crucial
system providing calcium regulation in the body [1].
Responding to the need of studies on the relationship
with vitamin D levels and parathyroid hormone in terms
of vitamin D deficiency definition, we have planned this
study in adults living in Turkey. We aimed to contribute to
the literature by determining the deflection point of intact
parathyroid hormone (iPTH) level compared to 25(OH)D3
level for determining the cut-off value of vitamin D defi-
ciency in Turkish adults.
Materials and methods
Study design and population
The results of the patients between 18 and 65 years of
age who had calcium (Ca), inorganic phosphate (P), cre-
atinine, iPTH and 25-hydroxy vitamin D3 tests at inpa-
tient and outpatient clinics of Okmeydani Training and
Research Hospital between the dates of 01/03/2015 and
01/03/2016 which were requested simultaneously and
performed in Okmeydani Training and Research Hospital
Medical Biochemistry laboratory were scanned retrospec-
tively via laboratory software system (ALIS, Ventura Soft-
ware Inc., Ankara, Turkey). For our study, ethical approval
dated 17.05.2016 with the number 478 has been received
from the Ethics Committee of our hospital.
In order to demonstrate the relationship between
vitamin D and iPTH more accurately, 1684 (1428 female and
256 male) patients who had iPTH levels within reference
ranges together with Ca, P and creatinine which affects this
system of the tests requested simultaneously and whose
25(OH)D3 levels were below 80 ng/mL (200 nmol/L) were
included in the study. Thus, a patient with parathyroid dis-
eases and/or kidney functional disorders that may cause
misinterpretation of our relationship between iPTH and
vitamin D has been excluded. Diseases such as osteopenia/
osteoporosis which are caused by vitamin D insufficiency
or deficiency have been included as they are not a reason
but a result of vitamin D deficiency. We were not able to get
the patient’s information about whether they use vitamin D
or not due to the retrospective nature of the study.
Analytes
Serum Ca level
It was measured photometrically by using CA2 kit (Roche
Diagnostics, Mannheim, Germany) in Cobas c702 (Roche
Diagnostics, Mannheim, Germany) analyzer. The refer-
ence interval for adults has been accepted as 8.4–10.2 mg/dL
(2.10–2.55 mmol/L). Inter-assay and intra-assay CVs for
Ca measurement were ≤2.0% and ≤2.5%, respectively.
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 Eren Vurgun et al.: Assessment of vitamin D deficiency level by PTH
Serum P level
It was measured photometrically by using PHOS2 kit
(Roche Diagnostics, Mannheim, Germany) in Cobas c702
(Roche Diagnostics, Mannheim, Germany) analyzer.
The reference interval for adults has been accepted as
2.7–4.5 mg/dL (0.85–1.45 mmol/L). Inter-assay and intra-
assay CVs for P measurement were ≤1.0% and ≤1.4%,
respectively.
Serum creatinine level
It was measured colorimetrically by using CREJ2 kit (Roche
Diagnostics, Mannheim, Germany) with Jaffe method in
Cobas c702 (Roche Diagnostics, Mannheim, Germany)
analyzer. The reference range for adults has been accepted
as 0.72–1.25 mg/dL (63–110 μmol/L) in males and 0.57–
1.11 mg/dL (50–98 μmol/L) in females. Inter-assay and
intra-assay CVs for creatinine measurement were ≤2.5%
and ≤3.7%, respectively.
Serum intact PTH level
It was measured by using iPTH kit (Roche Diagnostics,
Mannheim, Germany) with electrochemiluminescent
immunoassay method in Cobas e602 (Roche Diagnostics,
Mannheim, Germany) analyzer. The physiological refer-
ence range for adults has been accepted as 15–65 pg/mL
(1.6–6.9 pmol/L). Inter-assay and intra-assay CVs for iPTH
measurement were ≤2.0% and ≤3.4%, respectively.
Plasma 25(OH)D3 level
By using Zivak 25-OH Vitamin D2/D3 LC-MS/MS analysis
kit (Zivak Technologies, Istanbul, Turkey) it was measured
in ONH-100 liquid chromatography – mass spectrometry/
mass spectrometry analyzer (Zivak Technologies, Istan-
bul, Turkey). Inter-assay and intra-assay CVs for 25(OH)D3
measurement were ≤3.4% and ≤4.4%, respectively.
As 25(OH)D3 level of 80 ng/mL (200 nmol/L) and over
is accepted as toxicity risk, the values over 80 ng/mL were
not included in the study.
Statistical analysis
25(OH)D3 levels were converted to normal distribution
by applying logarithmic transformation as they did not
3
show a normal distribution. In all analysis made in order
to compare 25(OH)D3 levels, log(25(OH)D3) data were used
(as a p value) but they were expressed as 25(OH)D3 data for
pellucidity and to reflect the reality better.
Two-way ANOVA and ANCOVA tests followed by Bon-
ferroni test for post-hoc comparisons were used to analyze
the effects of 25(OH)D3, iPTH and the season on each other.
Pearson correlation coefficient was used to determine the
correlation between 25(OH)D3 and PTH.
In order to determine discussed deficiency start-
ing level, 25(OH)D3 levels were first classified as 80–50,
50–30, 30–25, 25–20, 20–15, 15–10, 10–5, 5–0 ng/mL
and iPTH levels among those groups were compared by
one-way ANOVA test. Afterwards post-hoc comparisons
were performed with the Fisher’s Least Significant Differ-
ence (LSD) test. In 25(OH)D3 group clusters, each group
includes its own lower limit value and does not include its
own upper limit value.
All statistical analyses were performed using the SPSS
software package, Version 17.0 (SPSS Inc., Chicago, IL,
USA). For all analyses, values of p < 0.05 were considered
significant.
Results
A significant effect of the season was observed on
25(OH)D3, whereas there was no significant effect of gender
in two-way ANOVA analysis which was conducted to
analyze the effects of the season and gender on 25(OH)D3
levels (p = 0.048 and p = 0.11, respectively) (Table 1).
When the 25(OH)D3 levels according to the seasons
were analyzed in pairwise comparisons with Bonferroni
test, the only difference was observed between spring and
winter (p = 0.033) (Table 2).
A significant effect of 25(OH)D3 was observed on iPTH,
whereas there was no significant effect of the season
in ANCOVA analysis which was conducted to analyze
the effects of the season and 25(OH)D3 on iPTH levels
(p < 0.001 and p = 0.11, respectively) (Table 3).
There was a significant reverse correlation between
25(OH)D3 and iPTH (r = −0.171, p < 0.001). As a result of the
one-way ANOVA test which was made to make comparisons
of iPTH levels according to 25(OH)D3 levels groupings as
80–50, 50–30, 30–25, 25–20, 20–15, 15–10, 10–5, 5–0 ng/mL,
significant difference among groups was determined
(p < 0.001).
In Fisher’s LSD tests which were performed post-
hoc in order to determine significant differences in iPTH
levels; first significant difference was determined between
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4 Eren Vurgun et al.: Assessment of vitamin D deficiency level by PTH

Table 1: Effects of season and gender on 25(OH)D3 level.

Source Sum of squares df Mean square F p-Value

Corrected model 2.11a 7 0.30 3.76 <0.001

Intercept 892.32 1 892.32 11107.30 <0.001
Season 0.64 3 0.21 2.64 0.048
Gender 0.19 1 0.19 2.47 0.11
Season*gender 0.10 3 0.03 0.43 0.72
Error 134.64 1676 0.08
Total 2416.16 1684
Corrected total 136.75 1683

R = 0.015 (adjusted R2 = 0.011).

a 2

Table 2: 25(OH)D3 and iPTH levels according to the seasons.

Spring (n = 719) Summer (n = 414) Autumn (n = 294) Winter (n = 257)

25(OH)D3 (ng/mL) 16.7 ± 11.3 18.0 ± 12.4 17.8 ± 11.3 20.8 ± 13.5a
iPTH (pg/mL) 42.5 ± 11.3 41.5 ± 11.3 42.4 ± 11.9 43.2 ± 11.5

p = 0.033 when compared to spring, data were expressed as mean ± standard deviation.
a

Table 3: Effects of 25(OH)D3 levels and season on iPTH level.

Source Sum of squares df Mean square F p-Value

Corrected model 7197.95a

4 1799.49 14.12 <0.001
Intercept 235717.84 1 235717.84 1848.98 <0.001
25(OH)D3 6700.43 1 6700.43 52.56 <0.001
Season 759.92 3 253.31 1.99 0.114
Error 214048.16 1679 127.48
Total 3242820.50 1684
Corrected total 221246.11 1683

R = 0.033 (adjusted R2 = 0.030).

a 2

25(OH)D3 groups of 80–50 and 50–30 ng/mL (p = 0.007). Discussion

No significant difference between 25(OH)D3 groups of
50–30 vs. 30–25, 30–25 vs. 25–20, 25–20 vs. 20–15 and
20–15 vs. 15–10 ng/mL was determined (p = 0.75, p = 0.74,
p = 0.40 and p = 0.67, respectively). Second and third sig-
nificant differences were determined between 25(OH)D3
groups of 15–10 and 10–5 ng/mL and between 10–5 and
5–0 ng/mL, respectively (p = 0.006 and p = 0.035, respec-
tively) (Figure 1).
At this stage; groups which had no significant dif-
ferences in between were combined and the second and
third points where iPTH increase response was seen were
combined because they were consecutive. Thus, three dif-
ferent groups which had 80–50, 50–10 and 10–0 ng/mL
of 25(OH)D3 levels and which did not remain 95% confi-
dence intervals of each other were formed according to the
response of iPTH. Significant differences were observed
between these groups (p < 0.001 for each) (Figure 2).
Today, vitamin D insufficiency and deficiency is regarded
as epidemic all over the world [3]. There is an increasing
interest in the physiological, pathological, therapeutic
and laboratory dimensions of 25(OH)D all over the world.
Herewith, there has been a dramatic increase of 25(OH)D
test requests in the recent years up to 80–90% [21, 22].
Therefore, the cost increase has also been a matter of issue
[23]. For these reasons, it is highly crucial to make correct
diagnosis for vitamin D insufficiency or deficiency.
As 25(OH)D level in the blood has a longer half-
life (~15 days) and a more loose regulation compared to
vitamin D (1,25(OH)2D), it is accepted as the best indica-
tor indicating the vitamin D depots in the body [24, 25].
As well as 1,25(OH)2D have a tighter regulation with the
stimulating effects of iPTH, calcium and phosphorus, it
also has a relatively shorter biological half-life (~15 h) in

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 Eren Vurgun et al.: Assessment of vitamin D deficiency level by PTH 5

50.0

p = 0.006*
47.2

p = 0.67
45.0 p = 0.74
p = 0.007*
44.5

42.2
41.8
iPTH (pg/mL)

41.0 41.0
40.6
40.0 p = 0.035*

p = 0.40
35.9
p = 0.75
35.0

p = 0.23

30.0
80–50 50–30 30–25 25–20 20–15 15–10 10–5 5–0
(n = 47) (n = 168) (n = 121) (n = 211) (n = 300) (n = 373) (n = 367) (n = 97)

25(OH)D3 (ng/mL)

Figure 1: iPTH levels in accordance to 25(OH)D3 level grouping *p < 0.05.

Values were given as mean and the error bars represent 95% CI.

46.0
p = 0.001* 45.1
44.0

42.0
41.6
iPTH (pg/mL)

40.0

38.0
p < 0.001*
36.0 35.9

34.0

32.0

30.0
80–50 50–10 10–0
(n = 47) (n = 1173) (n = 464)
25(OH)D3 (ng/mL)

Figure 2: iPTH deflection points formed by regrouping 25(OH)D3 levels according to iPTH levels *p < 0.05.
Values were given as mean and the error bars represent 95% CI.

the blood [24, 25]. The PTH response occurs via the cal-
cium-sensing receptor due to calcium absorption under
the control of active vitamin D in bloodstream [26].
Levels of 25(OH)D have been shown to vary according
to gender and season in some studies [27–30]. However,
in some studies, two of them in Turkey, there was no dif-
ference between genders [31–33]. We have also found that
gender has no effect on vitamin D when assessed with
seasons. When we compare the 25(OH)D3 levels according
to the seasons; we found that the average 25(OH)D3 levels
in winter were higher than in spring. Choi et al. [34] also
found the lowest 25(OH)D season as spring. Unlike other
studies [27, 30, 31, 35], we could not find any significant dif-
ferences between summer or autumn and winter or spring
seasons. Although we do not know the exact cause of this
finding, it could be a factor that the winter months had

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6 Eren Vurgun et al.: Assessment of vitamin D deficiency level by PTH
the lowest population (n = 257) in seasons. It should also
be noted that the 15 days of the first and last months of the
seasons actually reflect the previous and next months due
to the half-life of 25(OH)D is 15 days. In our study, it may
also be due to the inadequate or excess number of patients
in the 15-day periods of the first and last months of the
relevant seasons. The lack of seasonal effect on PTH levels
in our study also supports the lack of seasonal vitamin D
level differences.
In our study, when we evaluated iPTH responses given
to the reduction in 25(OH)D3 levels; we determined signifi-
cant iPTH increases firstly when 25(OH)D3 levels decreased
under 50 ng/mL, secondly decreased under 10 ng/mL and
thirdly decreased under 5 ng/mL. In the light of these find-
ings; we can state that iPTH levels are suppressed when
25(OH)D3 over 50 ng/mL, remains stable when 25(OH)D3
levels in between 50 and 10 ng/mL and gives the first
increase response when 25(OH)D3 falls below 10 ng/mL. If
vitamin D deficiency and insufficiency definitions should
be made for adult Turkish population, we believe that
it is not appropriate to make definition of insufficiency
without having clinical information and risks. However,
we think that it is not possible for metabolic homeostasis
to respond to vitamin D deficiency which is mostly syn-
thesized endogenously. Thus, we can say that 10 ng/mL
is the cut-off level of 25(OH)D3 deficiency that metabolism
gives reaction to it. However, in order to be able to define
vitamin D insufficiency, we think that the results of pro-
spective studies which evaluate future disease risks
should be compiled.
It should be noted that; it has been revealed that
there are differences between study methods of meas-
ured 25(OH)D levels. In a study conducted by Sadat-Ali
et al. [36], when the 25(OH)D levels were measured by
HPLC-LC/MS, all of the vitamin D deficient participants
had an increased PTH. Nevertheless, when the same par-
ticipants’ 25(OH)D levels were measured by CLIA and RIA,
vitamin D deficient participants showed normal PTH at
a high ratio [36]. As LC-MS/MS method -the gold stand-
ard- was used for the measurement of 25(OH)D3 levels in
our study, it can be said that the levels which found in our
study are more accurate and reliable when compared to
studies using other methods.
Another difference of our study from other studies
is that we gave only the 25(OH)D3 levels as a result not
total 25(OH)D levels. However, this does not constitute a
limitation for the population of Turkey. The most substan-
tial vitamin D compounds are vitamin D2 (ergocalciferol)
which found in plants and consumed as a supplement or
in fortified foods, and vitamin D3 (cholecalciferol) which
is synthesized in the human skin under the influence of
sunlight or consumed in oily fish, fortified foods or as a
supplement [37]. Although there are no vitamin D2 sup-
plemented foods in Turkey, the main source of vitamin
D is vitamin D3 which is synthesized endogenously via
sunlight exposure. When we take a look at the literature,
there are not many studies which distinguish 25(OH)D2
and 25(OH)D3 measurements. In the study conducted by
Schleicher et al. [38] in American population over 15.652
people, it was indicated that only 19% of people included
to the study had a detectable level (>0.8 ng/mL) of 25(OH)D2
levels. They stated that most of these people, especially
those over 60 years of age, were the ones who had been
prescribed vitamin D2 supplementation. They found the
mean level of 25(OH)D2 of people who were under the age
of 60 and whose 25(OH)D2 were detectable as 1.9 ng/mL
[38]. Again, in a recent study mean level of 25(OH)D2 of
1068 people was determined as approximately 0.7 ng/mL
[39]. The results of these studies support us for the fact
that 25(OH)D2 levels will not change the results of our
study.
A limitation of our study was that it was not known
whether the patients included in the study received
vitamin D supplements or not. However, the majority
of patients had 25(OH)D3 levels of <50 ng/mL and the
average of 25(OH)D3 levels of all patients was low (17.9
ng/mL), which suggest that most of the patients have not
received vitamin D supplements. In addition, although
the low number of individuals in the group with 25(OH)D3
levels of 50–80 ng/mL seems to be a limitation in terms
of statistical analysis, we think this is not a disadvantage
because this group constitutes only 2.8% (n = 47) of all
patients and it is suitable for population distribution.
Another issue to be considered in the studies examin-
ing relationship between 25(OH)D and PTH is, the active
form 1,25(OH)2D which has a much shorter half-life has
an effect on the iPTH which has a ~4 min of half-life [40]
while 25(OH)D levels with a half-life of 15 days are still
unchanged. The low correlations between 25(OH)D and
PTH in our study and in many other studies [41] may also
be a result of this situation. This situation should be con-
sidered when evaluating the physiological PTH response
to vitamin D deficiency. This, in fact, indicates that the
use of personal reference intervals for PTH will be more
accurate.
In conclusion, we believe that cut-off value for
vitamin D deficiency in Turkish adults at all seasons
depending on iPTH response should be used as 10 ng/mL.
For the cut-off value required to be used in the diagnosis
of vitamin D insufficiency, the results of clinical studies
in which risk factors are evaluated should be taken into
consideration.
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 Eren Vurgun et al.: Assessment of vitamin D deficiency level by PTH
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